Treatment of diseases of the ocular anterior segment and ocular surface of the eye are traditionally treated by self-application of topical drops from drug solution or other vehicles to the surface of the eye. However, self-administration of eye drops to the eye is both inconvenient and inefficient, particularly with elderly and pediatric patients because the eye drops must be self-administered daily or multiple times daily to effectively treat the disease or condition. Many patients have an aversion to self-administering topical eye drops. In cases where the drug is in the form of a suspension or an emulsion, temporary blurred vision often results from administration. Topically applied drugs may also result in unwanted ocular side effects such as general discomfort, “burning”, “stinging”, ocular surface redness, hyperemia, and foreign body sensation. All of these factors contribute to a lack of compliance with topical eye drops in ocular drug therapy, particularly in the case of glaucoma where therapeutic intervention is life-long and continuous.
Data demonstrate that many patients are unable to self-administer eye drops to effectively treat their disease or condition, particularly the elderly and pediatric patients. Hennessy A. L. et al. “A Video Study of Drop Instillation in Both Glaucoma and Retina Patients with Visual Impairment.” Am. J. Ophthalmol. 2011; 152(6):982-988. Patient questionnaires have shown that patients are unable to effectively self-dose and administer eye drops accurately and as prescribed by physicians. Robin, et al. “Adherence in glaucoma: objective measurements of once-daily and adjunctive medication use.” Am. J. Ophthalmol. 2007; 144(4):533-540. These studies have also demonstrated that only 71% of 204 glaucoma patients were able to properly administer a drop into the eye, and only 39% of patients did so without touching the bottle to the surface of the eye. Hennessy A. L. et al. “A Video Study of Drop Instillation in Both Glaucoma and Retina Patients with Visual Impairment.” Am. J. Ophthalmol. 2011; 152(6):982-98.
Ocular hypertension or elevated IOP occurs when the pressure inside the eye is higher than normal. Eye pressure is usually expressed in millimeters of mercury, (mm Hg) or kPa. Normal eye pressure is generally considered to be between 12-21 mm Hg, this “normal” upper limit may vary in patient populations to 22 mm Hg. In the healthy eye, a clear fluid called aqueous humor circulates inside the front (30, see FIGS. 1A, 1C) portion of the eye. To maintain a constant healthy eye pressure, the eye continually produces a small amount of aqueous humor while an equal amount of this fluid flows out of the eye. The fluid flows out of the eye through a complex network of cells and tissue in an area called the drainage angle. These include the trabecular meshwork and the endothelial cells of Schlemm's canal, which together control pressure dependent aqueous humor outflow (see 22 FIG. 1C). A pressure independent pathway for aqueous humor outflow is located in the anterior portion of the ciliary muscle (see 24 of FIG. 1C). If the aqueous humor does not flow through the chamber angle properly, fluid pressure builds in the eye, causing ocular hypertension or elevated IOP. Ocular hypertension can also result if the eye produces too much aqueous humor. Injury to the eye can also cause ocular hypertension, as can certain eye diseases. Population groups most susceptible to ocular hypertension are patients with a family history of ocular hypertension or glaucoma, patients with diabetes, patients over the age of forty years old, people of African descent and myopic patients.
Ocular hypertension or elevated IOP is not the same as glaucoma. Glaucoma refers to a family of diseases of the eye usually caused by high intraocular pressure. However, a patient may have elevated IOP and not suffer from glaucoma. Glaucoma is generally divided between open angle glaucoma and closed angle glaucoma. Open angle chronic glaucoma is more common, is usually painless, and develops slowly over time and often has no symptoms until the disease has progressed significantly. Open angle glaucoma is usually treated with glaucoma medication to lower the intraocular pressure. Closed-angle glaucoma involves sudden eye pain resulting from a sudden spike in intraocular pressure, and is treated as a medical emergency. Glaucoma can permanently damage vision in the affected eye(s), first by decreasing peripheral vision and then potentially leading to blindness if left untreated.
Elevated intraocular pressure (above 21 mmHg or 2.8 kPa) is the most important and the only modifiable risk factor for glaucoma. The term “low tension” or “normal tension glaucoma” refers to patients with optic nerve damage and associated visual field loss, but normal or low intraocular pressure. Glaucoma has been called the “silent thief of sight” because the loss of vision often occurs gradually over a long period of time, and symptoms often occur only when the disease is quite advanced. Once lost, vision cannot normally be recovered, so treatment is aimed at preventing further loss. Worldwide, glaucoma is the second-leading cause of blindness after cataracts.
Ocular hypertension and glaucoma are usually treated with topical eye drops administered once or twice a day to control elevated IOP. These eye drops usually consist of compounds such as alpha agonists, beta-blockers, cholinergic agents, prostaglandin analogs and combinations of these compounds. While these compounds are effective at lowering IOP, these compounds have the disadvantage of having to be topically applied by self-administration to the front (30, FIGS. 1A and 1C) of the eye once or twice a day. Along with significant patient compliance issues, daily use of such compounds often result in side effects such as surface hyperemia, or redness to the eye, which cause patients to stop using the drugs. The maximum reduction in IOP by drug treatment is typically up to a 30% lowering in elevated IOP.
Ocular implants are another method of lowering elevated IOP. Ocular implants are surgically implanted in the eye and release an IOP lowering drug on a continuous basis for a period of usually three to six months and then the implant must be replaced. The advantages of ocular implants are that once inserted into the eye, the drug is automatically administered. Disadvantages of ocular implants are they are surgically invasive and require replacement every three to six months which amounts to additional surgery. Many patients also have an aversion to injection of ocular implants into their eye and prefer topical drops.
Another class of compounds that has been shown to lower IOP are prostanoid EP2 agonists. While many prostanoid EP2 agonists are effective at lowering IOP in patients with elevated IOP and glaucoma, there are significant side effects associated with EP2 agonists that preclude their use as a daily-administered drug, such as thickening of the corneal epithelium and cellular infiltration into the aqueous humor. These side effects frequently occur when an EP2 agonist is applied topically to the eye every day and on a continuous basis. If these side effect issues could be overcome, the use of an EP2 agonist as an IOP lowering drug would be an attractive alternative to other commercially available compounds.